Introduction:

Proton pump inhibitors are one of the most frequently prescribed
classes of drug in the world because they combine a high level of
efficacy with low toxicity. In 2006, expenditure on these drugs was
£7bn globally.1 Yet studies consistently show that proton pump
inhibitors are being overprescribed worldwide in both primary and
secondary care.2 Between 25% and 70% of patients taking these
drugs have no appropriate indication. This means that, at the very
least, £100m from the National Health Service (NHS) budget and
almost £2bn worldwide is being spent unnecessarily on proton
pump inhibitors each year

The first generic proton pump inhibitor (omeprazole) was
introduced in 2002 and now comprises more than four fifths of all
prescriptions for proton pump inhibitors in India. In the five years
since the introduction of omeprazole, prescriptions for proton
pump inhibitors have doubled, although the reasons for this rise
are not obvious.3 Despite this substantial increase in drug usage,
the decrease in price means that overall expenditure on proton
pump inhibitors has been falling in recent years.

Effective and less expensive alternative drugs, such as H2 receptor
antagonists are available for many patients. Yet prescriptions for
proton pump inhibitors have superseded those for all other acid
inhibiting agents and now account for over 90% of the NHS drug
budget for treating dyspepsia. Proton pump inhibitors cost more
than other agents, which is partly why prescribing guidelines
have been drafted in several countries. The National Institute for
Health and Clinical Excellence (NICE) published its guidelines
on proton pump inhibitors in 2000. Its recommendations for using
these drugs particularly in the long term are relatively selective.4
If prescriptions were restricted to the recommended indications, expenditure on proton pump inhibitors would be far less than 90%
of the total dyspepsia drug budget.

Proton pump inhibitors have been a tremendous therapeutic
advance. Especially in the long term, they have transformed
the lives of patients with previously intractable symptoms of
gastro-oesophageal reflux with its associated complications,
and they have also proved valuable for patients who are at risk
of iatrogenic upper gastrointestinal pathology. A short term trial
of a proton pump inhibitor is also a good option for treating a
wide range of acid-peptic conditions. But the drugs are clearly
being overused. Some people will point to their combination of
superior efficacy and high safety as a justification for using them
in preference to drugs such as H2 receptor antagonists. Yet, side
effects should not be overlooked. An increase in the prevalence of
pneumonia and Campylobacter enteritis is reported, as well as a
doubling of the risk of infection with Clostridium difficile.5 Acute
interstitial nephritis and osteoporosis are unusual but recognised
consequences of treatment with proton pump inhibitors.6 Such
effects are fortunately rare. The adverse effect of over prescription
on drug budgets around the world is the real problem. Quite how
to motivate doctors to follow guidelines is a matter of considerable
importance

Proton pump inhibitors & Hypomagnesemia :

Proton pump inhibitors (PPIs) were introduced to the market for
peptic ulcer disease in 1989. Hypomagnesemia was reported for the
first time in medical literature as a potential side effect of this class
of drugs in 2006. The US Food and Drug Administration released
a warning in 20111 about low serum magnesium levels associated
with long-term use of PPIs. An analysis of the Food and Drug
Administration’s Adverse Event Reporting System shows that
approximately 1% of patients experienced hypomagnesemia while
on PPIs.7 Symptoms include seizures, arrhythmias, hypotension,
tetany, and death.8 Despite the evidence, hypomagnesemia related
to chronic PPI use was not addressed in the 2013 American College
of Gastroenterology guidelines.9

PPIs are widely used, both through prescription and over the
counter, and are believed to be safe; however, one of the rare but
serious complications is hypomagnesemia. It is well reported
in nephrology journals.10 however, the paucity in the internal
medicine literature is amazing and prompted us to present this
case. To our knowledge, there have been only 4 case reports of PPI-
induced hypomagnesemia resulting in seizures.11 Magnesium is
excreted via renal and gastrointestinal routes. The prime culprit in
PPI-induced hypomagnesemia is impaired intestinal absorption.12
In patients with gastrointestinal malabsorption, H2 antagonists
should be the first-line therapy, or if PPI use is essential, then
the patient should be monitored closely for hypomagnesemia,
especially for cardiac patients who might have a propensity for
arrhythmia. There is a clear correlation between long-term use of
PPI and hypomagnesemia, and clinicians need to be aware of it.

Hypomagnesemic hypoparathyroidism may develop during
long-term PPI therapy.1, 2 Patients can be asymptomatic or
present with life-threatening arrhythmias and neuromuscular
symptoms; furthermore, hypomagnesemia is refractory to
magnesium supplementation until PPIs are withdrawn.13 Dietary
magnesium is largely absorbed in the small bowel, and kidneys
play a highly efficient role in its conservation, with 3% of filtered
magnesium lost in the urine, most of which is reabsorbed in
the thick ascending limb of the loop of Henley. Mechanisms
by which the intestinal and renal handling of magnesium is
affected by PPIs are unknown. PPI-induced hypochlorhydria is
postulated to impair magnesium solubilization and absorption in
the small intestine, ultimately depleting its body stores.14 Variant
alleles of active magnesium transport ion channel TRPM6/7 are
associated with subtle malabsorption or persistent leak through
the kidneys, which may be further aggravated by PPIs.15 This
might explain why only a minority of PPI-treated patients develop
Hypomagnesemic Hypoparathyroidism. However, the lack of any
report of hypomagnesemia associated with H2-blockers does not
support a mechanistic role of hypochlorhydria in PPI-induced
hypomagnesemia.

Hypomagnesemic hypoparathyroidism has been reported with
different PPIs, and our patient had ongoing hypomagnesemia
with both omeprazole and pantoprazole. The potential to trigger
a subclinical magnesium depletion or an overt deficiency status
seems to be a class effect that may apply to all PPIs.16 If PPI-
associated hypomagnesemia is dose-related and if it can recur
with rechallenge remains unclear.17 We underscore the need for
close monitoring of blood magnesium levels during long-term
PPI therapy. PPI therapy is a rare but fully reversible cause of
unexplained hypoparathyroidism

Proton Pump Inhibitors and Risk of Fractures

Concerns have been raised about the risk of fractures with
acid-suppressive medications, such as proton pump inhibitors
and histamine2-receptor antagonists. In this meta-analysis of
observational studies, proton pump inhibitors modestly increased
the risk of hip, spine, and any-site fractures, whereas histamine2-
receptor antagonists were not associated with fracture risk. The
possibility of residual confounding cannot be excluded. Further
skeletal evaluation should be considered for patients who are
taking proton pump inhibitors and also at risk for osteoporotic
fracture.

National Institute for Clinical Excellence. Guidance on the use
of proton pump inhibitors (PPI) inthetreatmentofdyspepsia.2000.
www.nice.org.uk/newsevents/pressreleases/pressreleasearchive/
pressreleases2000/2000_022_nice_issues_guidance_on_proton_
pump_inhibitors_ppi_for_dyspepsia.jsp